Ceramides and response to dual secondary hormonal therapy in metastatic castration-resistant prostate cancer (mCRPC) among Black men.

Multiple reports suggest that Black patients with mCRPC have different responses to radiation, immunotherapy, chemotherapy, and secondary hormonal therapy compared with White patients with mCRPC. In our prospective trial of combination therapy with apalutamide (Apa) and abiraterone acetate (AA) plus prednisone (P) among Black and White men with mCRPC (PANTHER, ClinicalTrials.gov identifier NCT03098836), we previously reported the 24-month radiographic progression-free survival (rPFS) for Black and White men were 61% (95% CI 49, 78) and 38% (95% CI 27, 54), while the 36-month overall survival (OS) rates were 68% (95% CI 55, 83) and 50% (95% CI 37, 66), respectively. Our previously reported exploratory genome-wide analysis identified genetic ancestry-related single nucleotide polymorphisms in genes that were known to play a role in ceramide metabolism that associated with time to prostate specific antigen (PSA) progression on AA + P therapy in mCRPC. Ceramides are associated with cancer biology and therapeutic outcomes, with ceramide Cer(d18:1/20:0), in particular, having been reported as a biomarker for colon cancer. Ceramide Synthase 4 (CerS4), which produces Cer(d18:1/20:0), has been reported to be associated with worse prognosis in colorectal cancer. We therefore hypothesized that expression of distinct ceramide species may be associated with rPFS or OS among Black and White patients with mCRPC treated with combination Apa and AA + P in the PANTHER study. Serum from 37 White and 28 Black patients enrolled in the PANTHER study who had fasted for 8-12 hours was collected and evaluable at baseline. Metabolomic profiling was done using the Biocrates MxP Quant 500 Kit. Median levels for each of 26 ceramides were calculated using the study population and used as a cut point. Cox proportional hazard models were used to calculate the hazard ratio for rPFS and OS associated with above or below median ceramide expression. Models were stratified by race. In the PANTHER study, among Black patients, expression of Cer(d18:1/20:0) was associated with rPFS (HR 4.02; 95% CI 1.06, 15.2; p value = 0.041), but there was no significant association found among White patients. Expression of Cer(d18:1/20:0) was also associated with improved OS among Black patients (HR 4.82; 95% CI 1.51, 15.4; p = 0.008), but there was no significant association found among White patients. No significant associations were found with any other ceramides. Our study showed that Cer(d18:1/20:0) associated with prolonged rPFS and OS among Black patients with mCRPC treated with the combination of Apa and AA + P therapy. Pending validation, this distinct ceramide species has potential to serve as a predictive indicator of response to combination Apa and AA + P therapy among Black mCRPC patients. Drug and funding for Abi Race and PANTHER provided by Janssen Scientific Affairs, LLC.

Duke Scholars

Author Andrew John Armstrong Medicine, Medical Oncology

Author Susan Halabi Biostatistics & Bioinformatics, Division of Biostatistics

Author Daniel James George Medicine, Medical Oncology